A subject of the present invention is quinoline derivatives, in particular endowed with inhibitory properties of human immuno-deficiency virus integrase.
It also relates to a synthetic process for these derivatives and their biological uses.
The integration of the genomic DNA of HIV in the chromosomes of the infected cell is strictly necessary for the replication of the virus. The viral enzyme which catalyzes the integration of the viral DNA in the chromatin of the host is integrase. Consequently, an integrase inhibitor constitutes ipso facto a candidate for blocking infection by HIV, and possibly an effective therapeutic agent. Of the three viral enzymes which condition the replication of HIV, namely reverse transcriptase, protease and integrase, integrase is the last not to be targeted by any therapeutic agent. In the context of polytherapy, which currently seems to be only method of effectively combatting the rapid development of the virus, obtaining an integrase inhibitor is an essential objective.
Various groups across the world have developed integrase inhibitors, some of these molecules have submicromolar inhibitory activities in vitro, such as quercetagenin. Other compounds had promising activities such as phenyl ethyl esters of caffeic acid, cosalane, 5,8-dihydroxy-1,4-naphthoquinone, cucurmin, 1,10-phenanthroline, primaquine, chloroquine, certain derivatives of podophyllotoxin or also bis-gallic esters. However, the activites of these different products have only been reported in vitro and these products have not been shown to be active in vivo.
More recently, bis-caffeates of quinic acid have been described as active in vivo but depending on protocols involving bringing the drug into contact with the virus beforehand.
The work of inventors in this field has led them to study quinoline derivatives and to demonstrate anti-integrase properties in vitro as well as in vivo, these properties being accompanied by significant innocuity.
A subject of the invention is therefore to provide new quinoline derivatives capable in particular of inhibiting the integrase activity of HIV in vitro and in vivo.
It also relates to a synthetic process for these derivatives which can be easily implemented on an industrial scale.
A subject of the invention is also to exploit the anti-integrase properties of these derivatives for the development of medicaments.
The derivatives according to the invention are characterized in that they correspond to the general formula I 
in which
Ra, Rb and Rc, identical or different from one another, represent one or more substituents, themselves identical or different, occupying any position on the rings, this or these substituents being chosen from a xe2x80x94(CH2)nxe2x80x94Y or xe2x80x94CHxe2x95x90CHxe2x80x94Y group, where Y represents a halogen atom, an xe2x80x94OH, xe2x80x94OR, xe2x80x94COH, xe2x80x94COR, xe2x80x94COOH, xe2x80x94COOR, xe2x80x94COH, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CON(Rx, Ry)xe2x80x94CHxe2x95x90NOH, xe2x80x94COxe2x80x94CHxe2x95x90NOH, xe2x80x94NH2, xe2x80x94N(Rx, Ry), xe2x80x94NO2, xe2x80x94PO(OR)2xe2x80x94SH2, xe2x80x94SR, xe2x80x94SO2R, xe2x80x94SO2NHR, CN, or Z(Rc) radical, where R represents an alkyl radical with 1 to 8 carbon atoms, or an aryl or heterocyclic radical, Rx and Ry, identical or different, represent an alkyl radical with 1 to 5 carbon atoms, Z represents an aryl or heterocyclic radical and n is zero or an integer between 1 and 5,
Rb moreover can represent a hydrogen atom,
and when Y represents a xe2x80x94COOH or xe2x80x94COOR group in Rc, Z, if it represents an aryl group, includes at least 3 substituents or the quinoline ring is trisubstituted,
X represents an ethylene double bond; or a group chosen from xe2x80x94(CH2)nxe2x80x94, where n is an integer between 1 and 5; xe2x80x94CH(Rd)xe2x80x94CH(Re)xe2x80x94, Rd and Re, identical or different, representing a hydrogen atom, a halogen atom, a hydroxy or epoxy group; xe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94C(O)xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94C(O)xe2x80x94Oxe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94NQxe2x80x94(CH2)mxe2x80x94, or xe2x80x94(CH2)nxe2x80x2xe2x80x94S(O)txe2x80x94(CH2)mxe2x80x94, where nxe2x80x2 is an integer from 0 to 8, m is an integer from 0 to 8, t is zero or an integer equal to 1 or 2, and Q is a hydrogen atom, or an alkyl or aryl radical,
as well as the pharmaceutically acceptable salts of these derivatives, their diastereoisomeric forms and their enantiomeric forms.
By xe2x80x9carylxe2x80x9d radical is meant a phenyl or naphthyl radical. xe2x80x9cHeterocyclicxe2x80x9d designates rings with 5 or 6 elements comprising one, two, three or four heteroatoms, chosen from N, S or O. xe2x80x9cHalogenxe2x80x9d designates a fluorine, chlorine, bromine atom, or a tritralogeno-methyl group, in particular trichloromethyl. xe2x80x9cAlkylxe2x80x9d without further explanation designates a radical with 1 to 5 carbon atoms.
A preferred family of derivatives according to the invention comprises at least one ethylene double bond.
In particular, derivatives in which Ra and/or X represent an ethylenically unsaturated group are concerned.
In a preferred group of this family, X represents an ethylene double bond, and Ra represents a group chosen from xe2x80x94CHxe2x95x90CHxe2x80x94COOH, xe2x80x94CHxe2x95x90CHxe2x80x94COOR, xe2x80x94CHxe2x95x90CHxe2x80x94COH, xe2x80x94CHxe2x95x90CHxe2x80x94COR, xe2x80x94CHxe2x95x90CHxe2x80x94CONH2, xe2x80x94CON(Rx, Ry), and xe2x80x94CHxe2x95x90CHxe2x80x94Z(Rc).
In another group of this family, X represents a xe2x80x94CH(Rd)xe2x80x94CH(Re)xe2x80x94, or xe2x80x94(CH2)nxe2x80x94 group, and Ra has the meaning given in relation to the above group.
In yet another group, X represents an ethylene double bond and Ra is a radical chosen from xe2x80x94OH, xe2x80x94COOH, or a pharmaceutically acceptable salt, or CN.
Products of this group have the formula II 
in which
Ra represents at least one substituent chosen from an xe2x80x94OH, xe2x80x94COOH group, or a pharmaceutically acceptable salt, or CN, preferably two substituents one of which is an xe2x80x94OH group and the other has one of the above meanings,
Rc represents two or three xe2x80x94OH substituents.
In another preferred family of the invention, the quinoline derivatives do not include an ethylene double bond.
A preferred group of this family is constituted by derivatives in which Ra represents a xe2x80x94(CH2)nxe2x80x94Y group and X is a xe2x80x94CH(Rd)xe2x80x94CH(Re)xe2x80x94, or xe2x80x94(CH2)nxe2x80x94 group.
In another preferred group of this family, X comprises a heteroatom. This concerns in particular products in which X is a group chosen from xe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94C(O)xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94C(O)xe2x80x94Oxe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94N(Q)xe2x80x94(CH2)mxe2x80x94, or xe2x80x94(CH2)nxe2x80x2xe2x80x94S(O)txe2x80x94(CH2)mxe2x80x94, where nxe2x80x2 is an integer from 0 to 8, m is an integer from 0 to 8, t is zero or an integer equal to 1 or 2, and Q represents a hydrogen atom, an alkyl or aryl radical.
Particularly advantageous products according to the invention include 2-[2-[(3,4-dihydroxyphenyl)ethenyl]]quinoline, 8-hydroxy-2-[2-[(3,4-dihydroxyphenyl)ethenyl]]quinoline, 8-hydroxy-2-[2-[(3,4-dihydroxyphenyl)ethenyl]]7-quinoline carboxylic acid, the sodium salt of 8-hydroxy-2-[2-[(3,4-dihydroxyphenyl)ethenyl]]7-quinolinecarboxylic acid, 7-cyano-8-hydroxy-2-[2-[(3,4-dihydro-xyphenyl)ethenyl]]quinoline, 8-hydroxy-2-[2-[(3.4,5-trihydroxyphenyl)ethenyl]]7-quinoline carboxylic acid, and 2-[2-[(3,4-dihydroxyphenyl)ethenyl]]5,7-quinolinedicarboxylic acid.
The invention also relates to a synthetic process for the derivatives defined above.
This process is characterized in that it comprises
the reaction of a quinaldine of formula III with an aromatic or heteroaromatic derivative of formula IV carrying the appropriate blocking groups: 
in which A and B represent reactive groups capable of generating group X as defined above, Ra, Rb, Rc and Z having the meaning given with regard to formula I, but including blocking groups, and
the elimination of the protective groups.
According to an embodiment of the invention, in order to obtain quinoline derivatives in which X does not represent a heteroatom,
a Perkin-type condensation between a quinaldine of formula V and an aromatic or heteroaromatic derivative of formula VI carrying the appropriate blocking groups was used: 
in which the different substituents have the meanings given with regard to formula I, but carrying blocking groups, and
the protective groups are eliminated.
The operation is carried out under reflux in a pyridine-water mixture for approximately 2 hours to 3 days.
In order to prepare for example derivatives corresponding to formula II, a quinaldine of formula V in which Ra represents at least one substituent chosen from the xe2x80x94OH, or xe2x80x94COOH group, or an oxime, and preferably two substituents, one of which is an xe2x80x94OH group, and the other has one of the meanings above, is advantageously reacted with an acetoxybenzaldehyde of formula VII: 
in which Rc represents at least two xe2x80x94OH groups blocked by protective groups.
The condensation stage leads to the formation of quinoline derivatives comprising a double bond represented by X in formula I, and can be treated, if desired, according to standard techniques, to introduce the desired substituents Rd and Re.
The blocking groups are eliminated by hydrolysis.
According to another embodiment of the invention, in order to obtain quinoline derivatives in which X comprises a heteroatom, a quinaldine derivative or formula VIII is used 
in which W represents xe2x80x94NH2, xe2x80x94NH(Q)xe2x80x94OH, xe2x80x94PO3H2, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CO2H or xe2x80x94CHO, Q representing a hydrogen atom, an alkyl or aryl radical;
or a quinaldine derivative of formula IX 
in which Wa represents xe2x80x94Cl, xe2x80x94Br, xe2x80x94NH2, xe2x80x94OH or xe2x80x94NH(Q) where Q represents a hydrogen atom or an alkyl or aryl radical, and Wb represents xe2x80x94H.
More specifically, the following respective reactions were used, with coupling of
a quinaldine derivative of formula VIII in which W=OH, with a derivative of formula X:
Z(Rc)(CH2)nCOCl, according to the diagram 
the reaction being avantageously carried out in a pyridine medium,
a quinaldine derivative of formula IX in which the xe2x80x94CH group (Wa, Wb) represents xe2x80x94CH2-NH2, with a derivative of formula XI,
OHC (CH2)nZ(Rc), according to the diagram 
the reaction being avantageously carried out in the presence of NaBH3CN in an acetic acid medium,
a quinaldine derivative of formula IX in which the xe2x80x94CH group (Wa, Wb) represents a xe2x80x94CH2Br group, with a derivative of formula XII, NaS(CH2)Z(Rc), advantageously in the presence of dichloromethane, the coupling being followed by reaction with sodium periodate in order to obtain the corresponding sulphoxide, and, if desired, reacting the sulphoxide with KHSO5 in order to obtain the corresponding sulphone, according to the diagram 
The quinoline derivatives used as starting products in these syntheses are commercially available or easily accessible by synthesis for a person skilled in the art.
Thus, for example, the derivatives of formula VIII in which W represents xe2x80x94NH2 can be obtained by a process comprising:
condensation of an aromatic amine 1 with an aldehyde 2, by treatment in an acid medium, for example (6N HCl) and heating according to a Doebner-Miller reaction,
oxidation of quinoline 3 by metachloroperbenzoic acid (mcpba), in a dichloromethane medium, for approximately 14 hours, at ambient temperature, which leads to the N-oxide 4,
activation of the N-oxide 4 by tosyl chloride (TsCl), in a chloroform medium, at ambient temperature, for approximately 3 hours, followed by treatment with ammonium hydroxide, leading to 2-aminoquinoline 5 being obtained.
This process is illustrated by the following diagram 
In order to obtain the derivatives of formula VIII in which W represents Cl, a quinoline 3 is reacted with sodium hypochlorite, which allows a 2-hydroxyquinoline derivative 6 to be obtained, the treatment of which by phosphorous oxychloride produces 2-chloroquinoline 7.
This process is illustrated by the following diagram: 
In order to obtain derivatives of formula VIII in which W represents xe2x80x94COOH, a process comprising the following is advantageously used:
condensation of an amine 1 and an aldehyde 8 in an acid medium (for example 6N HCl) and heating, which produces quinaldine 9,
oxidation of the methyl by selenium dioxide in order to obtain aldehyde 10, (for example in a dioxane medium and heating), and by enforcing the acid conditions 11. As a variant, the reducing amination of the aldehyde by the cyanoborohydride in an acetic medium produces aminomethylquinoline 12.
This process is illustrated by the following diagram: 
In these formulae, the substituents are defined as indicated above.
In order to obtain quinoline derivatives of formula VIII in which X represents a xe2x80x94CH (Wa, Wb) group with Wa=Br and Wb=H, the bromination of the methyl of quinaldine 9, for example using N-bromosuccinimide, (NBS), which produces compound 13 is advantageously carried out.
This reaction is illustrated by the following diagram: 
Study of the biological properties of the derivatives of the invention showed an inhibitory activity vis-à-vis HIV integrase and the EcoRI enzyme in vitro. Experiments carried out in vivo have furthermore shown their inhibitory effect on the replication of HIV and the absence of effect on the late phases of the replication of HIV. These results are thus extremely interesting for the treatment of an infection by this virus, especially as the toxicity studies have shown the significant innocuity of these derivatives.
The invention thus relates to pharmaceutical compositions characterized in that they contain an effective quantity of at least one derivative as defined above, in combination with pharmaceutically acceptable vehicles.
These compositions are advantageously used in combination with other anti-HIV medicaments, in particular medicaments endowed with an inhibitory effect vis-à-vis the reverse transcriptase and/or protease.
The doses and administration methods are adapted as a function of the single-drug, two-drug or three-drug combination therapy treatment used.
The invention also relates to the use of the derivatives defined above as biological reagents usable in particular for mechanism studies concerning the viral infection.